Metabolism circuit information processing method, metabolism circuit information processor, program, and recording medium

ABSTRACT

An apparatus according to this invention allows a user to set at least one of desired metabolic circuit information, environmental factor information, and end condition information, changes all of nodes and edges included in the metabolic circuit information or either the nodes or the edges based on at least one of the metabolic circuit information set by simulation condition setting and the environmental factor information until the end condition information set by the simulation condition setting is satisfied, executes a metabolic simulation by a metabolic flux balance analysis, and outputs a result of the simulation executed by simulation execution.

TECHNICAL FIELD

The present invention relates to a metabolic circuit informationprocessing method, a metabolic circuit information processing apparatus,a program, and a recording medium. More specifically, the presentinvention relates to a metabolic circuit information processing method,a metabolic circuit information processing apparatus, a program, and arecording medium that can simulate a metabolic circuit by a metabolicflux balance analysis.

BACKGROUND ART

In recent years, studies in analysis of a metabolic circuit forcontrolling metabolism such as fermentation are developing. The analysisof the metabolic circuit is intended to clarify what behavior a complexcircuit exhibits and what functional properties the circuit possessesunder various conditions. To attempt in-depth analysis of theseproperties, however, it is necessary to measure the structure of themetabolic circuit and constants (hereinafter, “reaction constants”)related to respective reactions and the like. In respect of metaboliccircuits, though limited to metabolism of partial model organisms suchas colon bacilli and yeasts, metabolic circuit information databasessuch as EcoCyc and KEGG are constructed. However, it is not easy tomeasure reaction constants of respective metabolic reactions, andinformation stored in the databases is insufficient. Therefore, it isquite significant to develop a method of obtaining knowledge as much aspossible only based on the structure of a metabolic reaction circuitwithout using information on the reaction constants.

A metabolic analysis has been proposed by Kacser & Burns (Kacser, H. andBurns, J., Genetics, 97, 639-666, 1981), Heinrich & Rapoport (Heinrich,R. and Rapoport, T, Eur. J. Biochem., 42, 89-95, 1974), and the others,and developed by researchers such as Fell (Fell, D.: Understanding theControl of Metabolism, Portland Press, London, 1996, Fell, D. Biochem.J., 286, 313-330, 1992).

The metabolic flux balance analysis (“FBA”) is an approach belonging tothe study of this metabolic analysis. In the metabolic FBA, even ifconstants related to metabolism cannot be measured sufficiently, abehavioral range and properties of a target metabolic circuit areanalyzed based on fundamental constraint conditions such as the law ofconservation of mass while using only structures of metabolic reactions.

A basic approach for the FBA made by Palsson et al., for example, is todescribe metabolic reactions as simultaneous linear equations, and todefine a vector space of a solution of the simultaneous equations. Thisvector space is transformed into a biochemically important basis, and ametabolic state for maximizing an objective function given by linearprogramming is finally specified (Shilling, C. and Palsson, B., Proc.Nat. Sci. Acad., 95, 4193-4198, 1998).

This FBA basic approach is applied to Haemophilus influenzae Rd(Edwards, J. and Palsson, B., Journal of Biological Chemistry, 274, 25,17410-17416, 1999), E. coli K-12 (Edwards, J. and Palsson, B., BMCBioinformatics, 1, 1, 2000, Edwards, J. and Palsson, B., Biotechnologyand bioengineering, 58, Nos. 2 & 3, 162-169, 1998) and MG1655 (Edwards,J., Ibarra, R. and Paisson, B., Nature Biotechnology, 19, 125-130,2001), human red blood cells (Jamshidi, N., et al. Bioinformatics, 3,286-287, 2001), and the like, for carrying out metabolic circuitanalysis.

Nevertheless, these conventional approaches have the followingdisadvantage. Although the information on stationary-state metaboliccircuits stored in the metabolic circuit information databases can beacquired, information on a new metabolic circuit cannot be acquired.

In addition, these conventional approaches are disadvantageouslyincapable of acquiring information on an optimum metabolic circuit basedon the balance between a metabolic efficiency and a metabolic cost orthe like. Namely, none of the conventional approaches carry out asimulation by changing the information on the known stationary-statemetabolic circuits, and make selection or the like of an optimummetabolic circuit which may possibly fulfill a user's objective.

Specifically, the FBA approach made by Palsson et al. is excellent inthat only if the structure of the metabolic circuit is known from themetabolic circuit information databases or the like, many properties ofthe metabolic circuit can be identified based on the information onstationary-state metabolic circuits stored in the metabolic circuitinformation databases without the need of individual reaction constants.This approach has, however, a constraint that only the stationary-statemetabolic circuits can be analyzed.

Furthermore, from viewpoints of industrial applicability, conditionsthat should be actually considered, for example, information on aculture environment and the like such as culture time and cost are notat all taken into consideration in the conventional FBA approaches. Inaddition, none of the conventional FBA approaches select the optimummetabolic circuit based on the balance between the metabolic efficiencyand the cost or the like while using the information on the cultureenvironment in the analysis. Consequently, it is difficult to applyanalysis results obtained by the conventional approaches to actualexperimental operations and production of metabolisms which are actualobjectives of users.

In other words, none of the conventional approaches analyze a desiredmetabolic circuit in light of various environmental factors that have aneffect on metabolism, the culture time, the cost, and the like, andacquire new metabolic circuit information which may possibly fulfilluser's objective.

The conventional approaches for the metabolic circuit analysis have thusmany disadvantages. As a result, the conventional approaches areinferior in convenience of metabolic information processing result andimplementation efficiency for users who are to analyze metabolicinformation.

It is, therefore, an object of the present invention to provide ametabolic circuit information processing method, a metabolic circuitinformation processing apparatus, a program, and a recording medium thatcan acquire both of or one of information on a new metabolic circuit andinformation on a target optimum metabolic circuit.

DISCLOSURE OF THE INVENTION

One aspect of the present invention provides the metabolic circuitinformation processing method including: a metabolic circuit informationsetting step of allowing a user to set target metabolic circuitinformation that includes information on nodes respectively representingbasic constituent elements of a metabolism and edges respectivelyrepresenting reaction relationships among the basic constituentelements; an environmental factor information setting step of allowingthe user to set environmental factor information on an environmentalfactor that influences both of or one of the basic constituent elementsand the reaction relationships; an end condition information settingstep of allowing the user to set end condition information on acondition for finishing a simulation; a simulation execution step ofchanging both of or one of one of the nodes and one of the edgesincluded in the target metabolic circuit information, and of executing ametabolic simulation by a metabolic flux balance analysis using theenvironmental factor information set at the environmental factorinformation setting step; a simulation result determination step ofdetermining whether a result of the simulation executed at thesimulation execution step satisfies the end condition information set atthe end condition information setting step, and of, if the result of thesimulation does not satisfy the end condition information, changing bothof or one of another one of the nodes and another one of the edges,followed by execution of the simulation execution step; and a simulationresult output step of outputting the result of the simulation executedat the simulation execution step.

The method according to one aspect of the present invention allows auser to set target metabolic circuit information that includesinformation on nodes respectively representing basic constituentelements of a metabolism and edges respectively representing reactionrelationships among the basic constituent elements; allows the user toset environmental factor information on an environmental factor thatinfluences both of or one of the basic constituent elements and thereaction relationships; allows the user to set end condition informationon a condition for finishing a simulation; changes both of or one of oneof the nodes and one of the edges included in the target metaboliccircuit information, and executes a metabolic simulation by a metabolicflux balance analysis using the set environmental factor information;determines whether a result of the simulation satisfies the set endcondition information, and, if the result of the simulation does notsatisfy the end condition information, changes both of or one of anotherone of the nodes and another one of the edges, followed by execution ofthe simulation execution step; and outputs the result of the executedsimulation. Therefore, the user can easily set various conditionsaccording to a user's objective, and a user's target optimum metaboliccircuit information or new metabolic circuit information can be acquiredby performing a simulation processing. By user's setting, for example, atoxic matter such as dioxin or a persistent matter such as plastic as asubstrate (starting material) and obtaining information on an optimummetabolic circuit for metabolizing the substrate, the information can beused for biodegradation studies on toxic matters and persistent matters.In addition, if the user sets an intermediate metabolite or a finalmetabolite such as a low-molecular compound, a sugar, a protein, or anamino acid, then optimum metabolic circuit information for producingmetabolites can be acquired from a simulation result, andpharmaceuticals and foods can be produced using this metabolic circuitinformation. Furthermore, by setting a matter in vivo (e.g., a sugar, aprotein, an amino acid, a DNA, an RNA, or a signal transmitter) andacquiring the metabolic circuit information, knowledge related to adisease or the like caused by a metabolic disorder resulting from thematter in vivo can be acquired.

Another aspect of the present invention provides the metabolic circuitinformation processing method according to the above aspect, whereineach of the basic constituent elements includes information on at leastone of a substrate, a metabolite, and a matter in vivo.

This specifically depicts one example of the basic constituent elements.According to the method, each of the basic constituent elements includesinformation on at least one of a substrate, a metabolite, and a matterin vivo. Therefore, if the user sets an intermediate metabolite or afinal metabolite such as a low-molecular compound, a sugar, a protein,or an amino acid produced by microorganisms, pharmaceuticals,pharmaceutical intermediates, alcohols, amino acids, or the like can beproduced with high efficiency by acquiring optimum metabolic circuitinformation. Furthermore, by setting a matter in vivo (e.g., a sugar, aprotein, an amino acid, a DNA, an RNA, or a signal transmitter), newmetabolic circuit information related to various diseases and the likecan be acquired from the simulation result.

Still another aspect of the present invention provides the metaboliccircuit information processing method according to the above aspect,wherein the reaction relationships includes information on arelationship of at least one of an enzyme reaction, a transcriptioncontrol reaction, a translation control reaction, and a chemicalreaction between the basic constituent elements.

This specifically depicts one example of the reaction relationships.According to the method, each of the reaction relationships includesinformation on a relationship of at least one of an enzyme reaction, atranscription control reaction, a translation control reaction, and achemical reaction between the basic constituent elements. Therefore, inrelation to the enzyme reaction, for example, information on a syntheticrate and a decomposition rate for the enzyme reaction between asubstrate and a metabolite can be defined as edge information, andsimulation can be carried out based on the information. In relation tothe transcription control reaction, information such as a transcriptionrate, a transcription promoter, and a transcription inhibitor for thetranscription control reaction between a DNA and an RNA can be definedas edge information, and simulation can be carried out based on theinformation. In relation to the translation control reaction, atranslation rate, a translation promoter, and a translation inhibitorfor the translation control reaction between an mRNA and a protein canbe defined as edge information, and simulation can be carried out basedon the information. In relation to the chemical reaction, informationsuch as a structural change, a polymerization property, a stability, anda chemical equilibrium for the chemical reaction between metabolites canbe defined as edge information, and simulation can be carried out basedon the information.

Still another aspect of the present invention provides the metaboliccircuit information processing method according to the above aspect,wherein the environmental factor information includes information on atleast one of a temperature, a pH, an atmospheric pressure, the number oftimes of stirring, a dissolved oxygen quantity, a culture mediumcomponent, an optical condition, and a carbon dioxide concentration.

This specifically depicts one example of the environmental factorinformation. According to the method, the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration. Therefore, simulation can be carried outbased on information on an upper limit and a lower limit of atemperature, a pH, an atmospheric pressure, the number of times ofstirring, a dissolved oxygen quantity, culture medium components,optical conditions, a carbon dioxide concentration, or the like that isfeasible for an operation in a laboratory or a factory.

Still another aspect of the present invention provides the metaboliccircuit information processing method according to the above aspect,wherein the end condition information includes information on at leastone of a culture time, a metabolic efficiency, a metabolite quantity,the number of times of simulation, a cell density, a culture cost, a pH,a dissolved oxygen quantity, and a culture medium component quantity.

This specifically depicts one example of the end condition information.According to the method, the end condition information includesinformation on at least one of a culture time, a metabolic efficiency, ametabolite quantity, the number of times of simulation, a cell density,a culture cost, a pH, a dissolved oxygen quantity, and a culture mediumcomponent quantity. Therefore, if the culture time and the culture cost,for example, are set as the end condition information, the user can knowan optimum simulation result within user's desired ranges of the culturetime and the culture cost and thus, metabolic circuit information usablefor actual production can be acquired. In addition, if the metabolicefficiency and the metabolite quantity are set as the end conditioninformation, then simulation can be carried out until the metabolicefficiency and the metabolite quantity reach a target efficiency and atarget quantity, respectively, and metabolic circuit information such asculture medium components and culture time necessary to attain thetarget metabolic efficiency and the target metabolite quantity can beacquired. If the cell density, the pH, the dissolved oxygen quantity,and the culture medium component quantity are set as the end conditioninformation, then simulation can be carried out until they reach a setpH, a set culture medium component quantity, and the like, respectively,and metabolic circuit information in light of a change in a culturestate can be acquired. If the number of times of simulation is set asthe end condition information, optimum metabolic circuit information canbe acquired by executing simulation by a certain number of times.Therefore, the disadvantage in that it takes considerable longcalculation time to acquire the metabolic circuit information due to agreat calculation quantity can be avoided.

The metabolic circuit information processing method according to stillanother aspect of the present invention further includes: a mutationfrequency information storage step of storing mutation frequencyinformation on a frequency with which both of or one of the one node andthe one edge included in the metabolic circuit information mutates toboth of or one of another one of the nodes and another one of the edges,wherein at the simulation execution step, both of or one of the one nodeand the one edge included in the metabolic circuit information ischanged using the mutation frequency information stored at the mutationfrequency information storage step.

According to the method, mutation frequency information on a frequencywith which both of or one of the one node and the one edge included inthe metabolic circuit information mutates to both of or one of anotherone of the nodes and another one of the edges is stored. Both of or oneof the one node and the one edge included in the metabolic circuitinformation is changed using the stored mutation frequency information.Therefore, the metabolic circuit information can be efficiently changed.

Still another aspect of the present invention provides the metaboliccircuit information processing method according to the above aspect,wherein, at the simulation execution step, both of or one of the onenode and the one edge included in the metabolic circuit information ischanged using at least one of a genetic algorithm and simulatedannealing.

According to the method, both of or one of the one node and the one edgeincluded in the metabolic circuit information is changed using at leastone of a genetic algorithm and simulated annealing. Therefore, byapplying a known optimization algorithm, the user can efficientlyacquire optimum new metabolic circuit information other thanstationary-state metabolic circuit information.

The present invention relates to a metabolic circuit informationprocessing apparatus. Still another aspect of the present inventionprovides the metabolic circuit information processing apparatusincluding: a metabolic circuit information storage unit that storesmetabolic circuit information including information on nodesrespectively representing basic constituent elements of a metabolism andedges respectively representing reaction relationships among the basicconstituent elements; an environmental factor information storage unitthat stores environmental factor information on an environmental factorthat influences both of or one of the basic constituent elements and thereaction relationships; an end condition information storage unit thatstores end condition information on condition for finishing asimulation; a simulation condition setting unit that allows a user toset at least one of the metabolic circuit information, the environmentalfactor information, and the end condition information desired by theuser; a simulation execution unit that changes both of or one of one ofthe nodes and one of the edges included in the metabolic circuitinformation, and executes a metabolic simulation by a metabolic fluxbalance analysis based on at least one of the metabolic circuitinformation set by simulation condition setting unit and theenvironmental factor information until the end condition information setby the simulation condition setting unit is satisfied; and a simulationresult output unit that outputs a result of the simulation executed bythe simulation execution unit.

The apparatus according to still another aspect of the present inventionstores metabolic circuit information including information on nodesrespectively representing basic constituent elements of a metabolism andedges respectively representing reaction relationships among the basicconstituent elements; stores end condition information on a conditionfor finishing a simulation; stores environmental factor information onan environmental factor that influences both of or one of the basicconstituent elements and the reaction relationships; allows a user toset at least one of the metabolic circuit information, the environmentalfactor information, and the end condition information desired by theuser; changes both of or one of one of the nodes and one of the edgesincluded in the metabolic circuit information, and executes a metabolicsimulation by a metabolic flux balance analysis based on at least one ofthe set metabolic circuit information and the environmental factorinformation until the set end condition information is satisfied; andoutputs a result of the executed metabolic simulation. Therefore, theuser can easily set various conditions according to a user's objective,and a user's target optimum metabolic circuit information or newmetabolic circuit information can be acquired by performing a simulationprocessing. By user's setting, for example, a toxic matter such asdioxin or a persistent matter such as plastic as a substrate (startingmaterial) and obtaining information on an optimum metabolic circuit formetabolizing the substrate, the information can be used forbiodegradation of toxic matters and persistent matters. In addition, ifthe user sets an intermediate metabolite or a final metabolite such as alow-molecular compound, a sugar, a protein, or an amino acid, thenoptimum metabolic circuit information for producing metabolites can beacquired from a simulation result, and pharmaceuticals and foods can beproduced using this metabolic circuit information. Furthermore, bysetting a matter in vivo (e.g., a sugar, a protein, an amino acid, aDNA, an RNA, or a signal transmitter) and acquiring the metaboliccircuit information, knowledge related to a disease or the like causedby a metabolic disorder resulting from the matter in vivo can beacquired.

Still another aspect of the present invention provides the metaboliccircuit information processing apparatus according to the above aspect,wherein each of the basic constituent elements includes information onat least one of a substrate, a metabolite, and a matter in vivo.

This specifically depicts one example of the basic constituent elements.According to the apparatus, each of the basic constituent elementsincludes information on at least one of a substrate, a metabolite, and amatter in vivo. Therefore, if the user sets an intermediate metaboliteor a final metabolite such as a low-molecular compound, a sugar, aprotein, or an amino acid produced by microorganisms, pharmaceuticals,pharmaceutical intermediates, alcohols, amino acids, or the like can beproduced with high efficiency by acquiring optimum metabolic circuitinformation. Furthermore, by setting a matter in vivo (e.g., a sugar, aprotein, an amino acid, a DNA, an RNA, or a signal transmitter), newmetabolic circuit information related to various diseases and the likecan be acquired from the simulation result.

Still another aspect of the present invention provides the metaboliccircuit information processing apparatus according to the above aspect,wherein each of the reaction relationships includes information on arelationship of at least one of an enzyme reaction, a transcriptioncontrol reaction, a translation control reaction, and a chemicalreaction between the basic constituent elements.

This specifically depicts one example of the reaction relationships.According to the apparatus, each of the reaction relationships includesinformation on a relationship of at least one of an enzyme reaction, atranscription control reaction, a translation control reaction, and achemical reaction between the basic constituent elements. Therefore, inrelation to the enzyme reaction, for example, information on a syntheticrate and a decomposition rate for the enzyme reaction between asubstrate and a metabolite can be defined as edge information, andsimulation can be carried out based on the information. In relation tothe transcription control reaction, information such as a transcriptionrate, a transcription promoter, and a transcription inhibitor for thetranscription control reaction between a DNA and an RNA can be definedas edge information, and simulation can be carried out based on theinformation. In relation to the translation control reaction, atranslation rate, a translation promoter, and a translation inhibitorfor the translation control reaction between an mRNA and a protein canbe defined as edge information, and simulation can be carried out basedon the information. In relation to the chemical reaction, informationsuch as a structural change, a polymerization property, a stability, anda chemical equilibrium for the chemical reaction between metabolites canbe defined as edge information, and simulation can be carried out basedon the information.

Still another aspect of the present invention provides the metaboliccircuit information processing apparatus according to the above aspect,wherein the environmental factor information includes information on atleast one of a temperature, a pH, an atmospheric pressure, the number oftimes of stirring, a dissolved oxygen quantity, a culture mediumcomponent, an optical condition, and a carbon dioxide concentration.

This specifically depicts one example of the environmental factorinformation. According to the apparatus, the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration. Therefore, simulation can be carried outbased on information on an upper limit and a lower limit of atemperature, a pH, an atmospheric pressure, the number of times ofstirring, a dissolved oxygen quantity, culture medium components,optical conditions, a carbon dioxide concentration, or the like that isfeasible for an operation in a laboratory or a factory.

Still another aspect of the present invention provides the metaboliccircuit information processing apparatus according to the above aspect,wherein the end condition information includes information on at leastone of a culture time, a metabolic efficiency, a metabolite quantity,the number of times of simulation, a cell density, a culture cost, a pH,a dissolved oxygen quantity, and a culture medium component quantity.

This specifically depicts one example of the end condition information.According to the apparatus, the end condition information includesinformation on at least one of a culture time, a metabolic efficiency, ametabolite quantity, the number of times of simulation, a cell density,a culture cost, a pH, a dissolved oxygen quantity, and a culture mediumcomponent quantity. Therefore, if the culture time and the culture cost,for example, are set as the end condition information, the user can knowan optimum simulation result within user's desired ranges of the culturetime and the culture cost and thus, metabolic circuit information usablefor actual production can be acquired. In addition, if the metabolicefficiency and the metabolite quantity are set as the end conditioninformation, then simulation can be carried out until the metabolicefficiency and the metabolite quantity reach a target efficiency and atarget quantity, respectively, and metabolic circuit information such asculture medium components and culture time necessary to attain thetarget metabolic efficiency and the target metabolite quantity can beacquired. If the cell density, the pH, the dissolved oxygen quantity,and the culture medium component quantity are set as the end conditioninformation, then simulation can be carried out until they reach a setpH, a set culture medium component quantity, and the like, respectively,and metabolic circuit information in light of a change in a culturestate can be acquired. If the number of times of simulation is set asthe end condition information, optimum metabolic circuit information canbe acquired by executing simulation by a certain number of times.Therefore, the disadvantage in that it takes considerable longcalculation time to acquire the metabolic circuit information due to agreat calculation quantity can be avoided.

The metabolic circuit information processing apparatus according tostill another aspect of the present invention further includes: amutation frequency information storage unit that stores mutationfrequency information on a frequency with which both of or one of theone node and the one edge included in the metabolic circuit informationmutates to both of or one of another one of the nodes and another one ofthe edges, wherein the simulation execution unit changes both of or oneof the one node and the one edge included in the metabolic circuitinformation using the mutation frequency information stored by themutation frequency information storage unit.

This specifically depicts one example of the simulation execution unit.According to the apparatus, mutation frequency information on afrequency with which both of or one of the one node and the one edgeincluded in the metabolic circuit information mutates to both of or oneof another one of the nodes and another one of the edges is stored. Bothof or one of the one node and the one edge included in the metaboliccircuit information is changed using the stored mutation frequencyinformation. Therefore, the metabolic circuit information can beefficiently changed.

Still another aspect of the present invention provides the metaboliccircuit information processing apparatus according to the above aspect,wherein the simulation execution unit changes both of or one of the onenode and the one edge included in the metabolic circuit informationusing at least one of a genetic algorithm and simulated annealing.

This specifically depicts one example of the simulation execution unit.According to the apparatus, both of or one of the one node and the oneedge included in the metabolic circuit information is changed using atleast one of a genetic algorithm and simulated annealing. Therefore, byapplying a known optimization algorithm, the user can efficientlyacquire optimum new metabolic circuit information other thanstationary-state metabolic circuit information.

The present invention relates to a program. Still another aspect of thepresent invention provides the program for allowing a computer toexecute a metabolic circuit information processing method, including: ametabolic circuit information setting step of allowing a user to settarget metabolic circuit information that includes information on nodesrespectively representing basic constituent elements of a metabolism andedges respectively representing reaction relationships between the basicconstituent elements; an environmental factor information setting stepof allowing the user to set environmental factor information on anenvironmental factor that influences both of or one of the basicconstituent elements and the reaction relationships; an end conditioninformation setting step of allowing the user to set end conditioninformation on a condition for finishing a simulation; a simulationexecution step of changing both of or one of one of the nodes and one ofthe edges included in the target metabolic circuit information, and ofexecuting a metabolic simulation by a metabolic flux balance analysisusing the environmental factor information set at the environmentalfactor information setting step; a simulation result determination stepof determining whether a result of the simulation executed at thesimulation execution step satisfies the end condition information set atthe end condition information setting step, and of, if the result of thesimulation does not satisfy the end condition information, changing bothof or one of another one of the nodes and another one of the edges,followed by execution of the simulation execution step; and a simulationresult output step of outputting the result of the simulation executedat the simulation execution step.

The program according to still another aspect of the present inventionallows a user to set target metabolic circuit information that includesinformation on nodes respectively representing basic constituentelements of a metabolism and edges respectively representing reactionrelationships among the basic constituent elements; allows the user toset environmental factor information on an environmental factor thatinfluences both of or one of the basic constituent elements and thereaction relationships; allows the user to set end condition informationon a condition for finishing a simulation; changes both of or one of oneof the nodes and one of the edges included in the target metaboliccircuit information, and executes a metabolic simulation by a metabolicflux balance analysis using the set environmental factor information;determines whether a result of the simulation satisfies the set endcondition information, and, if the result of the simulation does notsatisfy the end condition information, changes both of or one of anotherone of the nodes and another one of the edges; and outputs the result ofthe executed simulation. Therefore, the user can easily set variousconditions according to a user's objective, and a user's target optimummetabolic circuit information or new metabolic circuit information canbe acquired by performing a simulation processing. By user's setting,for example, a toxic matter such as dioxin or a persistent matter suchas plastic as a substrate (starting material) and obtaining informationon an optimum metabolic circuit for metabolizing the substrate, theinformation can be used for biodegradation of toxic matters andpersistent matters. In addition, if the user sets an intermediatemetabolite or a final metabolite such as a low-molecular compound, asugar, a protein, or an amino acid, then optimum metabolic circuitinformation for producing metabolites can be acquired from a simulationresult, and pharmaceuticals and foods can be produced using thismetabolic circuit information. Furthermore, by setting a matter in vivo(e.g., a sugar, a protein, an amino acid, a DNA, an RNA, or a signaltransmitter) and acquiring the metabolic circuit information, knowledgerelated to a disease or the like caused by a metabolic disorderresulting from the matter in vivo can be acquired.

Still another aspect of the present invention provides the programaccording to the above aspect, wherein each of the basic constituentelements includes information on at least one of a substrate, ametabolite, and a matter in vivo.

This specifically depicts one example of the basic constituent elements.According to the program, each of the basic constituent elementsincludes information on at least one of a substrate, a metabolite, and amatter in vivo. Therefore, if the user sets an intermediate metaboliteor a final metabolite such as a low-molecular compound, a sugar, aprotein, or an amino acid produced by microorganisms, pharmaceuticals,pharmaceutical intermediates, alcohols, amino acids, or the like can beproduced with high efficiency by acquiring optimum metabolic circuitinformation. Furthermore, by setting a matter in vivo (e.g., a sugar, aprotein, an amino acid, a DNA, an RNA, or a signal transmitter), newmetabolic circuit information related to various diseases and the likecan be acquired from the simulation result.

Still another aspect of the present invention provides the programaccording to the above aspect, wherein each of the reactionrelationships includes information on a relationship of at least one ofan enzyme reaction, a transcription control reaction, a translationcontrol reaction, and a chemical reaction between the basic constituentelements.

This specifically depicts one example of the reaction relationships.According to the program, each of the reaction relationships includesinformation on a relationship of at least one of an enzyme reaction, atranscription control reaction, a translation control reaction, and achemical reaction between the basic constituent elements. Therefore, inrelation to the enzyme reaction, for example, information on a syntheticrate and a decomposition rate for the enzyme reaction between asubstrate and a metabolite can be defined as edge information, andsimulation can be carried out based on the information. In relation tothe transcription control reaction, information such as a transcriptionrate, a transcription promoter, and a transcription inhibitor for thetranscription control reaction between a DNA and an RNA can be definedas edge information, and simulation can be carried out based on theinformation. In relation to the translation control reaction, atranslation rate, a translation promoter, and a translation inhibitorfor the translation control reaction between an mRNA and a protein canbe defined as edge information, and simulation can be carried out basedon the information. In relation to the chemical reaction, informationsuch as a structural change, a polymerization property, a stability, anda chemical equilibrium for the chemical reaction between metabolites canbe defined as edge information, and simulation can be carried out basedon the information.

Still another aspect of the present invention provides the programaccording to the above aspect, wherein the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration.

This specifically depicts one example of the environmental factorinformation. According to the program, the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration. Therefore, simulation can be carried outbased on information on an upper limit and a lower limit of atemperature, a pH, an atmospheric pressure, the number of times ofstirring, a dissolved oxygen quantity, culture medium components,optical conditions, a carbon dioxide concentration, or the like that isfeasible for an operation in a laboratory or a factory.

Still another aspect of the present invention provides the programaccording to the above aspect, wherein the end condition informationincludes information on at least one of a culture time, a metabolicefficiency, a metabolite quantity, the number of times of simulation, acell density, a culture cost, a pH, a dissolved oxygen quantity, and aculture medium component quantity.

This specifically depicts one example of the end condition information.According to the program, the end condition information includesinformation on at least one of a culture time, a metabolic efficiency, ametabolite quantity, the number of times of simulation, a cell density,a culture cost, a pH, a dissolved oxygen quantity, and a culture mediumcomponent quantity. Therefore, if the culture time and the culture cost,for example, are set as the end condition information, the user can knowan optimum simulation result within user's desired ranges of the culturetime and the culture cost and thus, metabolic circuit information usablefor actual production can be acquired. In addition, if the metabolicefficiency and the metabolite quantity are set as the end conditioninformation, then simulation can be carried out until the metabolicefficiency and the metabolite quantity reach a target efficiency and atarget quantity, respectively, and metabolic circuit information such asculture medium components and culture time necessary to attain thetarget metabolic efficiency and the target metabolite quantity can beacquired. If the cell density, the pH, the dissolved oxygen quantity,and the culture medium component quantity are set as the end conditioninformation, then simulation can be carried out until they reach a setpH, a set culture medium component quantity, and the like, respectively,and metabolic circuit information in light of a change in a culturestate can be acquired. If the number of times of simulation is set asthe end condition information, optimum metabolic circuit information canbe acquired by executing simulation by a certain number of times.Therefore, the disadvantage in that it takes considerable longcalculation time to acquire the metabolic circuit information due to agreat calculation quantity can be avoided.

The program according to still another aspect of the present inventionfurther includes: a mutation frequency information storage step ofstoring mutation frequency information on a frequency with which both ofor one of the one node and the one edge included in the metaboliccircuit information mutates to both of or one of another one of thenodes and another one of the edges, wherein at the simulation executionstep, both of or one of the one node and the one edge included in themetabolic circuit information is changed using the mutation frequencyinformation stored at the mutation frequency information storage step.

According to the program, mutation frequency information on a frequencywith which both of or one of the one node and the one edge included inthe metabolic circuit information mutates to both of or one of anotherone of the nodes and another one of the edges is stored. Both of or oneof the one node and the one edge included in the metabolic circuitinformation is changed using the stored mutation frequency information.Therefore, the metabolic circuit information can be efficiently changed.

Still another aspect of the present invention provides the programaccording to the above aspect, wherein, at the simulation executionstep, both of or one of the one node and the one edge included in themetabolic circuit information is changed using at least one of a geneticalgorithm and simulated annealing.

This depicts one example of the simulation execution step. According tothe program, both of or one of the one node and the one edge included inthe metabolic circuit information is changed using at least one of agenetic algorithm and simulated annealing. Therefore, by applying aknown optimization algorithm, the user can efficiently acquire optimumnew metabolic circuit information other than stationary-state metaboliccircuit information.

Moreover, the present invention relates to a recording medium. Therecording medium according to still another aspect of the presentinvention records the program according to any one of the aspects of theinvention.

According to the recording medium, by allowing a computer to read andexecute the program recorded on the recording medium, the program can berealized using the computer and the same advantages as those of theprograms can be achieved.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a principle explanatory view for one example of a basicprinciple of a system according to the present invention; FIG. 2 is ablock diagram for one example of the configuration of the system towhich the present invention is applied; FIG. 3 is a conceptual view forone example of information stored in a metabolic information circuitdatabase 106 a; FIG. 4 is a conceptual view for one example ofinformation stored in an environmental factor information database 106b; FIG. 5 is a conceptual view for one example of information stored inan end condition information database 106 c; FIG. 6 is a block diagramfor one example of the configuration of a database creation unit 102;FIG. 7 is a block diagram for one example of the configuration of asimulation condition setting unit 102 b; FIG. 8 is a flowchart for oneexample of a main processing performed by the system; FIG. 9 is aflowchart for one example of a database creation processing performed bythe system; FIG. 10 is a flowchart for one example of a metaboliccircuit information database creation processing; FIG. 11 a flowchartfor one example of an environmental factor information database creationprocessing; FIG. 12 a flowchart for one example of an end conditioninformation database creation processing; FIG. 13 a flowchart for oneexample of a simulation condition setting processing performed by thesystem; FIG. 14 depicts one example of a metabolic circuit settingscreen output to an output device 114 by a processing performed by ametabolic circuit setting unit 102 g; FIG. 15 depicts one example of anenvironmental factor setting screen output to the output device 114 by aprocessing performed by an environmental factor setting unit 102 h; FIG.16 depicts one example of an end condition setting screen output to theoutput device 114 by a processing performed by an end condition settingunit 102 i; FIG. 17 is a flowchart for one example of a simulationprocessing performed by the system; FIG. 18 is a conceptual view in aninstance in which a simulation is carried out by a metabolic FBA afterperforming a knock-in (“KI”) processing or a knock-out (“KO”)processing; FIG. 19 depicts one example of a simulation result displayscreen output to the output device 114 for a metabolic circuitinformation processing apparatus 100; and FIG. 20 depicts one example ofthe simulation result display screen output to the output device 114 forthe metabolic circuit information processing apparatus 100.

BEST MODE FOR CARRYING OUT THE INVENTION

Exemplary embodiments of the metabolic circuit information processingmethod, the metabolic circuit information processing apparatus, theprogram, and the recording medium will be explained, with reference tothe accompanying drawings. The present invention is not limited by theembodiments.

[Outline of System]

The principle configuration of a system according to the presentinvention will be explained first, followed by the configuration,processings, and the like of the system. FIG. 1 is a principleexplanatory view for one example of the basic principle of the system,and conceptually depicts only units related to the present invention inthe system configuration.

The system is for acquiring information on an optimum metabolic circuitfor fulfilling a user's objective. A user first selects metaboliccircuit information on target metabolism (e.g., metabolic circuitinformation on alcohol fermentation of yeasts) from a metabolic circuitinformation database. The metabolic circuit information database may be,for example, a database that stores metabolic circuit informationacquired from external metabolic information databases such as KEGG orEcoCyc accessed through the Internet or may be a database created bystoring original metabolic circuit information therein. The metaboliccircuit information includes information on at least nodes and edges.The “nodes” represent herein basic constituent elements of themetabolism, for example, DNAs, RNAs, proteins, or metabolites. The“metabolites” represent herein metabolic intermediates and finalmetabolites. The “edges” represent herein reaction relationships amongthe constituent elements, for example, a relationship related to anenzyme reaction among the basic constituent elements, a relationshiprelated to a reaction for controlling DNA transcription, a relationshiprelated to a reaction for controlling translation from an mRNA to aprotein, and a relationship related to a chemical reaction between themetabolites.

The user next selects environmental factor information related to thetarget yeast fermentation from an environmental factor informationdatabase, and sets a value of the selected environmental factorinformation. The environmental factor information database may be adatabase obtained by extracting environmental factor information fromthe metabolic information database created in advance and storing theextracted information, or may be a database obtained by user's newlyadding original environmental factor information and storing the addedinformation therein. The “environmental factor information” includesherein, for example, a culture temperature, a pH of a culture solution,an internal atmospheric pressure of a culture vessel such as afermentor, the number of times of stirring the culture solution, aquantity of oxygen dissolved in the culture solution, quantities ofculture medium components such as a carbon source, a nitrogen source,and trace metals, optical conditions such as a luminous intensity, and acarbon dioxide concentration.

The user selects end condition information on a condition for finishingthe simulation from an end condition information database created inadvance, and sets a value of the information. The “end conditioninformation database” may be a database obtained by extractinginformation serving as end conditions from the metabolic circuitinformation database created in advance and storing the extractedinformation, or may be a database obtained by user's newly addingoriginal end condition information and storing the added information.The “end condition information” means herein, for example, thresholdinformation on at least one of the culture time, the metabolicefficiency, a quantity of a target metabolite, the number of times ofsimulations performed by the system, a cell density, a culture cost, thepH of the culture solution, the quantity of oxygen dissolved in theculture solution, and the quantities of culture medium components suchas the carbon source, the nitrogen source, and the trace metals.

If the user is thus completed with settings of various conditions for asimulation processing, the metabolic circuit information processingapparatus executes the simulation processing according to theseconditions. In the simulation processing, both of or one of one of thenodes and one of the edges of the metabolic circuit information selectedby the user is changed, a metabolic FBA is performed until a solutionsatisfies the end condition information, and the solution thus obtainedis stored. Changed portions of the node and the edge may be obtained by,for example, automatically selecting portions that may be highly likelychanged using a mutation database that stores information on nodes andedges that tend to mutate in metabolic circuits, or by user'sindividually designating portions. The changed portions may heappropriately determined and optimum solution may be searched by knownalgorithms such as a genetic algorithm and simulated algorithm.Respective processes of the simulation processing may be performed inparallel.

The metabolic circuit information processing apparatus edits asimulation result, creates simulation result screen data, and outputsthe data.

The basic concept of the present invention will be explained in moredetail, taking yeast as an example. The metabolic circuit related toyeast fermentation is thoroughly studied, and principal parts of thecircuit are understood though not completely. The metabolic circuitinformation processing apparatus specifies N pieces of environmentalfactor information considered to be related to the circuit. Theapparatus sets a function for defining an alcohol fermentationefficiency as the end condition information. The function may beproportional to an expression quantity of a specific gene (A) or may bea function f(X₀, X₁, . . . , X_(N)) for coupling of a plurality offactors. If a metabolic FBA approach is used, a solution set offermentation efficiencies at respective points in an N-dimensional spaceformed by N factors related to the fermentation and an optimum operationline maximizing the fermentation efficiencies is obtained from the givencircuit. The solution obtained herein is obtained from the givencircuit, i.e., the stationary-state metabolic circuit.

The metabolic circuit information processing apparatus automatically (orsemiautomatically) discovers a circuit that can further improve thefermentation efficiencies when the stationary-state circuit is changedby a method such as a genetic algorithm or simulated annealing. In thegenetic algorithm, for example, knock-in (“KI”) and knock-out (“KO”) ofgenes (nodes) are basically used as operation. In an all solutionsearch, the KI and KO of all genes (nodes) are tried. This processing isrepeatedly carried out until the end condition information is satisfied,and the optimum circuit at a time at which this end conditioninformation is satisfied is set as a solution.

This process enables setting conditions so as to avoid incomprehensivemutations and experiments that require high culture cost. In addition,this process enables obtaining the optimum circuit for both thefermentation efficiencies and the culture cost.

[System Configuration]

The configuration of the system for embodying these basic features willbe explained.

FIG. 2 is a block diagram for one example of the configuration of thesystem to which the present invention is applied. FIG. 2 conceptuallydepicts only units related to the present invention in the systemconfiguration. This system is constituted so that a metabolic circuitinformation processing apparatus 100 that processes metabolicinformation, and an external system 200 that provides databases on themetabolic information and the like and external analysis programs for ametabolic information search and the like are communicably connected toeach other through a network 300.

In FIG. 2, the network 300 functions to connect the metabolic circuitinformation processing apparatus 100 and the external system 200 to eachother, and is, for example, the Internet.

In FIG. 2, the external system 200 is connected to the metabolic circuitinformation processing apparatus 100 through the network 300, andfunctions to provide the external databases on the metabolic informationand the like, and websites for executing the external analysis programsfor a metabolic circuit search and the like to the user.

The external system 200 may be constituted as a WEB server, an ASPserver, or the like, and hardware of the external system 200 may includean information processing apparatus such as a commercially availableworkstation or personal computer, and accessories of the apparatus.Respective functions of the external system 200 are realized by a CPU, adisk device, a memory device, an input device, an output device, acommunication control device, and the like in the hardware configurationof the external system 200 as well as programs for controlling thesedevices, and the like.

In FIG. 2, the metabolic circuit information processing apparatus 100includes a control unit 102 such as the CPU for generally controllingentirety of the metabolic circuit information processing apparatus 100,a communication control interface unit 104 connected to a communicationdevice (not shown) such as a router connected to a communication line orthe like, an input and output control interface unit 108 connected to aninput device 112 and an output device 114, and a storage unit 106 thatstores various databases (a metabolic circuit information database 106a, an environmental factor information database 106 b, an end conditioninformation database 106 c, and a mutation database 106 d). Therespective units are communicably connected to one another througharbitrary communication lines. In addition, this metabolic circuitinformation processing apparatus 100 is communicably connected to thenetwork 300 through the communication device such as the router and awired or wireless communication line such as a dedicated line.

The various databases stored in the storage unit 106 are storage unitssuch as fixed disk devices, and store various programs, tables, files,databases, webpage files, and the like used for various processings.

Among the constituent elements of the storage unit 106, the metaboliccircuit information database 106 a is a metabolic circuit informationstorage unit that stores metabolic circuit information includinginformation on the nodes that represent the basic constituent elementsof the metabolism and the edges that represent reaction relationshipsamong the basic constituent elements.

FIG. 3 is a conceptual view for one example of the information stored inthe metabolic circuit information database 106 a. As shown in FIG. 3,the metabolic circuit information database 106 a stores indexinformation such as organism names, cell names, and metabolism names aswell as node information and edge information on every indexinformation.

The “node information” is information stored so that the nodes such asDNAs, RNAs, proteins, and metabolites are stored while they areassociated with additional information. The “additional information”means herein information such as operation conditions and physicalstructures of the nodes. The additional information on an enzyme, forexample, includes an optimum pH, an optimum temperature, a reactionrate, a three-dimensional structure of the enzyme, a temperature rangein which the enzyme is stable, and a pH range in which the enzyme isstable. The additional information on a DNA or an RNA includes athree-dimensional structure of the DNA or RNA, a name of a coded proteinand a function of the protein, transcription, translation promotion, andinhibitors. The additional information on a metabolite includes achemical structure, a molecular weight, analogues, and stability andtoxicity relative to temperature and light.

The “edge information” is information on a connection source node and aconnection destination node of each edge and additional information onthe information that are stored while making them correspond to eachother. The “additional information” on each edge includes, for example,a transcription factor type, and a DNA binding condition, atranscription rate, transcription promotion, transcription inhibitorsfor a transcription reaction between a node source DNA and a nodedestination RNA. The “additional information” on each edge alsoincludes, for example, translation rate, translation promotion,translation inhibitors for a translation reaction between a node sourcemRNA and a node destination protein. The “additional information” oneach edge further includes information on a structural change, apolymerization property, a stability, and a chemical equilibrium in achemical reaction between a node source metabolic intermediate and anode destination final metabolite.

The environmental factor information database 106 b is an environmentalfactor information storage unit that stores environmental factorinformation on environmental factors influencing both of or either oneof the basic constituent elements and the reaction relationships. FIG. 4is a conceptual view for one example of information stored in theenvironmental factor information database 106 b. The “environmentalfactor information” includes information on at least one of thetemperature, the pH, the atmospheric pressure, the number of times ofstirring, the dissolved oxygen quantity, the culture medium compound,the optical condition, and the carbon dioxide concentration.

The end condition information database 106 c is an end conditioninformation storage unit that stores end condition information onconditions for finishing a simulation. FIG. 5 is a conceptual view forone example of information stored in the end condition informationdatabase 106 c. The “end condition information” includes information onat least one of the culture time, the metabolic efficiency, themetabolite quantity, the number of times of simulations, the celldensity, the culture cost, the pH, the dissolved oxygen quantity, theculture medium component quantities.

The mutation database 106 d is a mutation frequency information storageunit that stores mutation frequency information on frequencies withwhich both of or one of one of the nodes and one of the edges includedin the metabolic circuit information mutates to both of or one ofanother node and another edge. The “mutation frequency information” isinformation stored so that both of or one of the nodes and the edgesincluded in the metabolic circuit information, and the mutationfrequencies are defined while associating them, and are stored in adescending order of mutation frequencies.

In FIG. 2, the communication control interface unit 104 controlscommunication between the metabolic circuit information processingapparatus 100 and the network 300 (or communication device such asrouter). The communication control interface unit 104 has a function ofcommunicating data with other terminals through a communication line.

In FIG. 2, the input and output control interface unit 108 controls theinput device 112 and the output device 114. As the output device 114, amonitor (including a home television set), a loudspeaker or the like canbe used (it is noted that the output device 114 is sometimes referred toas “monitor” hereafter). As the input device 112, a keyboard, a mouse, amicrophone, or the like can be used. The monitor also realizes apointing device function in cooperation with the mouse.

In FIG. 2, the control unit 102 includes an internal memory for storingvarious programs such as an OS (Operating System), programs forspecifying various processing procedures, and required data. Using theseprograms and the like, information processings for executing variousprocessings are performed. The control unit 102 functionallyconceptually includes a database creation unit 102 a, a simulationcondition setting unit 102 b, and a simulation unit 102 c.

The database creation unit 102 a is a database creation unit thatcreates various databases. The simulation condition setting unit 102 ballows the user to set at least one of desired metabolic circuitinformation, environmental factor information, and end conditioninformation. The simulation unit 102 c changes both of or one the onenode and the one edge included in the metabolic circuit informationuntil the end condition information set by the simulation conditionsetting unit is satisfied, and executes a metabolic simulation by themetabolic FBA.

FIG. 6 is a block diagram for one example of the configuration of thedatabase creation unit 102 a, and conceptually depicts only unitsrelated to the present invention in the configuration. The databasecreation unit 102 a includes a metabolic circuit information databasecreation unit 102 d, an environmental factor database creation unit 102e, and an end condition information database creation unit 102 f.

Among the constituent elements of the database creation unit 102 a, themetabolic circuit information database creation unit 102 d selectsmetabolic circuit related information such as enzyme information, genecontrol information, signal transmission information related to variousmetabolic circuits and metabolisms from the external metabolicinformation databases, and stores the selected information in themetabolic circuit information database 106 a.

The environmental factor information database creation unit 102 eselects environmental factor related information from the metaboliccircuit information database 106 a, and stores the selected informationin the environmental factor information database 106 b. Theenvironmental factor information database creation unit 102 e allows theuser to add new environmental factor information and stores the addedinformation.

The end condition information database creation unit 102 f selects endcondition related information from the metabolic circuit informationdatabase 106 a and stores the selected information in the end conditioninformation database 106 c. The end condition information databasecreation unit 102 f allows the user to newly add original end conditioninformation and stores the added information. Details of processingsperformed by the respective units will be explained later.

FIG. 7 is a block diagram for one example of the configuration of thesimulation condition setting unit 102 b, and conceptually depicts onlyunits related to the present invention in the configuration. Thesimulation condition setting unit 102 b includes a metabolic circuitsetting unit 102 g, an environmental factor setting unit 102 h, and anend condition setting unit 102 i.

Among the constituent elements of the simulation condition setting unit102 b, the metabolic circuit setting unit 102 g allows the user to settarget metabolic circuit information. The environmental factor settingunit 102 h allows the user to set the environmental factor information.The end condition setting unit 102 i allows the user to set the endcondition information on the simulation. Details of processingsperformed by the respective units will be explained later.

[System Processings]

One example of processings performed by the system according to theembodiment configured as explained above will next be explained withreference to FIGS. 8 to 20.

[System Main Processing]

The detail of a main processing performed by the system will beexplained with reference to the flowchart shown in FIG. 8.

The metabolic circuit information processing apparatus 100 firstexecutes a database creation processing to be explained later withreference to FIG. 9 by a processing performed by the database creationunit 102 a (at step SA-1).

The metabolic circuit information processing apparatus 100 then executesa simulation condition setting processing to be explained later withreference to FIG. 13 by a processing performed by the simulationcondition setting unit 102 b (at step SA-2).

The metabolic circuit information processing apparatus 100 executes asimulation processing to be explained later with reference to FIG. 17 bya processing performed by the simulation unit 102 c (at step SA-3). Themain processing of the system is thus finished.

[Database Creation Processing]

The detail of the database creation processing will be explained withreference to flowcharts shown in FIGS. 9 to 12. FIG. 9 is a flowchartfor one example of the database creation processing performed by thesystem according to this embodiment.

The metabolic circuit information processing apparatus 100 first createsthe metabolic circuit information database by a processing performed bythe metabolic circuit information database creation unit 102 d (at stepSB-1).

FIG. 10 is a flowchart for one example of a metabolic circuitinformation database creation processing. The metabolic circuitinformation database creation unit 102 d accesses the external databasesthrough the communication control interface unit 104 (at step SC-1), andacquires metabolic circuit information designated by the user throughthe input device 112 (at step SC-2). The metabolic circuit informationdatabase creation unit 102 d stores the acquired metabolic circuitinformation in a predetermined storage area of the metabolic circuitinformation database 106 a (at step SC-3).

Referring back to FIG. 9, the metabolic circuit information processingapparatus 100 creates the environmental factor information database by aprocessing performed by the environmental factor information databasecreation unit 102 e (at step SB-2).

FIG. 11 is a flowchart for one example of an environmental factorinformation database creation processing. The environmental factorinformation database creation unit 102 e accesses the metabolic circuitinformation database (at step SD-1), and extracts information serving asenvironmental factor information from the additional information on nodeinformation, that on edge information, and the like (at step SD-2). Theenvironmental factor information database creation unit 102 e displaysthe extracted environmental factor information on the output device 114and allows the user to input other environmental factor information (atstep SD-3), and stores the input information in the environmental factorinformation database 106 b (at step SD-4).

Referring back to FIG. 9, the metabolic circuit information processingapparatus 100 creates the end condition information database by aprocessing performed by the end condition information database creationunit 102 f (at step SB-3).

FIG. 12 is a flowchart for one example of an end condition informationdatabase creation processing. The end condition information databasecreation unit 102 f accesses the metabolic circuit information database(at step SE-1), and extracts information serving as end conditions fromthe additional information on the node information, that on the edgeinformation, and the like (at step SE-2). The end condition informationdatabase creation unit 102 f displays the extracted end conditioninformation on the output device 114 and allows the user to input otherend condition information (at step SE-3), and stores the inputinformation in the end condition information database 106 c (at stepSE-4). The database creation processing is thus finished.

[Simulation Condition Setting Processing]

The detail of the simulation condition setting processing will beexplained with reference to FIG. 13. FIG. 13 is a flowchart for oneexample of the simulation condition setting processing performed by thesystem according to this embodiment.

The metabolic circuit information processing apparatus 100 allows theuser to set target metabolic circuit information from the metaboliccircuit information stored in the metabolic circuit information database106 a by a processing performed by the metabolic circuit setting unit102 g (at step SF-1).

FIG. 14 depicts one example of a metabolic circuit setting screen outputto the output device 114 by the processing performed by the metaboliccircuit setting unit 102 g. As shown in FIG. 14, the metabolic circuitsetting screen includes an organism name and cell name input area MA-1,a reference button MA-2 for referring to cell information stored in themetabolic circuit information database 106 a, a metabolic circuit nameinput area MA-3, a reference button MA-4 for referring to the metaboliccircuit information stored in the metabolic circuit information database106 a, a metabolite name input area MA-5, a reference button MA-6 forreferring to metabolite information stored in the metabolic circuitinformation database 106 a, a setting end button MA-7, and the like.

If the user selects the reference buttons MA-2, MA-4, and MA-6 shown inFIG. 14 using the input device 112 while viewing the metabolic circuitsetting screen, the metabolic circuit setting unit 102 g displays themetabolic circuit information stored in the metabolic circuitinformation database 106 a on a display.

Thereafter, if the user completes inputting respective items of theinput areas MA-1, MA-3, and MA-5 using the input device 112 and thenselects the setting end button MA-7 while viewing the metabolic circuitsetting screen, the metabolic circuit setting unit 102 g stores theinput information in the storage unit 106.

The metabolic circuit setting unit 102 g accesses the metabolic circuitinformation database 106 a, and acquires the metabolic circuitinformation set by the user (at step SF-2).

The metabolic circuit information processing apparatus 100 allows theuser to set desired environmental factor information from theenvironmental factor information stored in the environmental factorinformation database 106 b by a processing performed by theenvironmental factor setting unit 102 h (at step SF-3). Namely, theenvironmental factor setting unit 102 h allows the user to set variousconditions for the simulation processing.

FIG. 15 depicts one example of an environmental factor setting screenoutput to the output device 114 by the processing performed by theenvironmental factor setting unit 102 h. As shown in FIG. 15,environmental factor setting screen includes environmental factor inputareas MB-1 to MB-4, a pull-down menu display area MB-5 for selectinginformation stored in the environmental factor information database 106b, a setting end button MA-6, and the like. The pull-down menu displayarea MB-5 displays, when the user indicates an arrow portion of one ofthe input areas MB-1 to MB-4 using the input device 112 such as themouse, selectable environmental factors below the indicated input areawhile being superposed one after another.

If the user completes inputting respective items of the input areas MB-1to MB-4 using the input device 112 and then selects the setting endbutton MB-6 while viewing the environmental factor setting screen shownin FIG. 15, the environmental factor setting unit 102 h stores the inputinformation in the storage unit 106.

The metabolic circuit information processing apparatus 100 allows theuser to set desired end condition information from the end conditioninformation stored in the end condition information database 106 c by aprocessing performed by the end condition setting unit 102 i (at stepSF-4). The end condition setting unit 102 i allows the user to setvarious conditions for finishing the simulation.

FIG. 16 depicts one example of an end condition setting screen output tothe output device 114 by the processing performed by the end conditionsetting unit 102 i. As shown in FIG. 16, the end condition settingscreen includes a culture time input area MC-1, a metabolic efficiencyinput area MC-2, a number-of-times-of-simulation input area MC-3, asetting end button MC-4, and the like.

If the user completes inputting respective items of the input areas MC-1to MC-3 using the input device 112 and then selects the setting endbutton MC-4 while viewing the end condition setting screen shown in FIG.16, the end condition setting unit 102 i stores the input information inthe storage unit 106. The simulation condition setting processing isthus finished.

[Simulation Processing]

The detail of the simulation processing will be explained with referenceto FIG. 17. FIG. 17 is a flowchart for one example of the simulationprocessing performed by the system according to this embodiment.

The simulation unit 102 c first accesses the mutation database 106 d (atstep SG-1), and acquires the mutation frequency information onfrequencies with which both of or one of the one node and the one edgeincluded in the metabolic circuit information mutates to both of or oneof another node and another edge (at step SG-2).

The simulation unit 102 c performs both of or one of a knock-in (KI)processing and a knock-out (KO) processing for the nodes and edges (atstep SG-3) based on the mutation frequency information.

“Both of or one of a knock-in (KI) processing and a knock-out (KO)processing” means to conduct both of or one of insertion (KI) andreduction (KO) for the nodes and the edges in the metabolic circuitinformation based on the mutation frequency information and the like.For example, the simulation unit 102 c conducts both of or one of theinsertion (KI) and the reduction (KO) for the nodes and the edges in thedescending order of mutation frequencies based on the mutation frequencyinformation and the like.

The simulation unit 102 c performs a metabolic FBA for the metaboliccircuit information changed by both of or one of the knock-in (KI)processing and the knock-out (KO) processing (at step SG-4). Namely, thesimulation unit 102 c changes both of or one of the one node and the oneedge included in the target metabolic circuit information, and executesthe metabolic simulation by the metabolic FBA using data on theenvironmental factor information thus set.

FIG. 18 is a conceptual view for when the simulation unit 102 c performsthe simulation by the metabolic FBA after performing both of or one ofthe knock-in (KI) processing and the knock-out (KO) processing. As shownin FIG. 18, the simulation unit 102 c performs the simulation by themetabolic FBA based on the metabolic circuit information for which bothof or one of the KI and KO processings is executed and the environmentalfactor information, and calculates the metabolic efficiency or the likeof the metabolic circuit after both of or one of the KI and KO.

For example, if a concentration of a metabolic product i, a metabolitesynthetic rate, a decomposition rate, a consumption rate of metabolicreactants necessary for growth and the like, a rate of a concentrationchange caused by the transfer of metabolites in system boundariesdefined for the analysis are set as the additional information on theedges, and if the metabolic circuit obtained by conducting both of orone of the KI processing and the KO processing to the nodes and edgesrelated to the additional information is represented by Equation 1;dX _(i) /dt=V _(syn) −V _(deg) −V _(use) ±V _(trans)  (Equation 1)

(wherein, X_(i) is the concentration of the metabolic product i, V_(syn)is the synthetic rate of the metabolite i, V_(deg) is the decompositionrate, V_(use) is the consumption rate of the metabolic reactantsnecessary for growth and the like, and V_(trans) is the rate of theconcentration change caused by the transfer of the metabolites in thesystem boundaries defined for analysis), the Equation 1 is furtherrepresented by a linear algebra. Thereafter, a basis of a resultantmatrix is transformed into a biochemically significant basis. Vectors ofthis basis correspond to specific metabolic pathways, respectively.Based on this basis, it is examined whether the metabolic circuit isoptimized for some function. For example, two variables related to theobjective function (metabolic efficiency or the like) are picked up, andan optimum metabolic balance is calculated for all points on planes ofthe two variables using linear programming. If highest metabolicefficiency is set as the end conditions, for example, a function havingthe highest metabolic efficiency is selected. As a selection method, aknown optimization algorithm such as the genetic algorithm or thesimulated annealing may be used.

The simulation unit 102 c determines whether a simulation result(solution) satisfies the end condition information set by the simulationcondition setting unit (at step SG-5). If the simulation result(solution) does not satisfy the end condition information, theprocessing returns to the step SG-2. Namely, the simulation unit 102 cdetermines whether the simulation result satisfies data on the endcondition information thus set. If determining that the simulationresult does not satisfy the data, the simulation unit 102 c changes bothof or one of another node and another edge and executes a simulation.

If determining that the simulation result satisfies the end conditioninformation, the simulation unit 102 c creates the simulation resultscreen data (at step SG-6), and outputs the created data to the outputdevice 114 (at step SG-7).

Each of FIGS. 19 and 20 depicts one example of a simulation resultdisplay screen output to the output device 114 for the metabolic circuitinformation processing apparatus 100. As shown in FIGS. 19 and 20, thesimulation unit 102 c outputs a changed metabolic circuit diagram, achanged numeric value, a metabolic efficiency, and the like as thesimulation results, in the form of graphs.

In the example of the simulation result display screen shown in FIG. 19(simulation result 1), a header includes an individual number MD-1, achanged metabolic circuit diagram MD-2 changed by this simulationprocessing, and a metabolic efficiency MD-3 calculated by the metabolicFBA based on the changed metabolic circuit diagram. As shown in FIG. 19,the metabolic circuit diagrams may be displayed while being sorted in anorder of metabolic efficiencies. In FIG. 19, the circuit diagramcorresponding to an individual number 1 is MD-5, and the metabolicefficiency of the metabolic circuit is MD-4. The circuit diagramcorresponding to an individual number 2 is MD-7, and the metabolicefficiency of the metabolic circuit is MD-6.

In the example of the simulation result display screen shown in FIG. 20(simulation result 2), the simulation unit 102 c includes a display areaME-1 for the metabolic circuit diagram that produces an optimumsimulation result, and display areas ME-2 to ME-5 for numerical valuesof various pieces of environmental factor information when the optimumsimulation result is produced. As shown in FIG. 20, both astationary-state (default) metabolic circuit and a changed metaboliccircuit may be discriminately displayed in the metabolic circuit diagramdisplay area ME-1, by indicating edges of the stationary-state (default)metabolic circuit by thin lines and nodes thereof by white circles orthe like, and by indicating edges of the changed metabolic circuit bybold lines and nodes thereof by black circles or the like. Thesimulation processing is thus finished.

[Other Embodiments]

Exemplary embodiments of the present invention are described above,however, variously modified embodiments other than the one described canbe made within the scope of the technical spirit of the appended claims.

Further, among the respective processings explained in the embodiments,all of or part of the processings explained to be performedautomatically may be performed manually or all of or part of theprocessings explained to be performed manually may be performedautomatically by a well-known method.

The processing procedures, control procedures, specific names,information including various pieces of registered data, parameters forsearch conditions, and the like, screen examples, and databaseconfigurations explained above or shown in the drawings may bearbitrarily changed unless specified otherwise.

The respective constituent elements of the metabolic circuit informationprocessing apparatus 100 shown in the drawings are functionallyconceptual, and the metabolic circuit information processing apparatus100 is not always required to be physically configured as shown in thedrawings.

For example, all of or arbitrary part of the processing functions of therespective servers provided in the metabolic circuit informationprocessing apparatus 100, particularly the respective processingfunctions performed by the control unit 102 can be realized by the CPU(Central Processing Unit) and programs interpreted and executed by theCPU, or can be realized as hardware based on wired logic. The programsare recorded on the recording medium to be explained later, andmechanically read by the metabolic circuit information processingapparatus 100 as needed.

The various databases and the like (the metabolic circuit informationdatabase 106 a, the environmental factor information database 106 b, theend condition information database 106 c, and the mutation database 106d) stored in the storage unit 106 are storage units such as memorydevices, for example, a RAM and a ROM, fixed disk devices, for example,a hard disk, a flexible disk, and an optical disk. They store variousprograms, tables, files, databases, webpage files, and the like used forvarious processings and provision of websites.

In addition, the metabolic circuit information processing apparatus 100may be realized by connecting peripherals such as a printer, a monitor,and an image scanner to an information processing apparatus such as aninformation processing terminal, for example, a well-known personalcomputer or workstation, and by installing software (including aprogram, data, or the like) for realizing the method of the presentinvention into the information processing apparatus.

The specific form of distribution and integration of the metaboliccircuit information processing apparatus 100 is not limited to thatshown in the drawings. All of or part of the metabolic circuitinformation processing apparatus 100 can be functionally or physicallydistributed or integrated in arbitrary units according to various loadsand the like. For example, each database may be constitutedindependently as an independent database device, and part of theprocessings may be realized using a CGI (Common Gateway Interface).

Further, the program according to the present invention can be stored ina computer readable recording medium. It is assumed herein that examplesof this “recording medium” include arbitrary “portable physical mediums”such as a floppy disk (registered trademark), a magneto-optical disk, aROM, an EPROM, an EEPROM, a CD-ROM, an MO, and a DVD, arbitrary “fixedphysical mediums” such as a ROM, a RAM, and an HD included in variouscomputer systems, and “communication mediums” that temporarily hold theprogram such as a communication line or a carrier wave used when theprogram is transmitted through the network represented by a LAN, a WAN,or the Internet.

The “program” is a data processing method described in an arbitrarylanguage or by an arbitrary description method, and the form of the“program” is not limited but may be a source code, a binary code, or thelike. The “program” is not limited to a program constituted as a singleprogram. Examples of the “program” include a program constituted to bedistributed as a plurality of modules or libraries, and a program thatfulfils its function in cooperation with another program represented bythe OS (Operating System). The specific configurations, readingprocedures, install procedures after reading, and the like of therespective devices shown in the embodiment for reading the recordingmedium may be well-known configurations and procedures.

Furthermore, the network 300 functions to connect the metabolic circuitinformation processing apparatus 100 and the external system 200 to eachother, and may include any one of, for example, the Internet, anIntranet, a LAN (which may be either wired or wireless), a VAN, apersonal computer communication network, a public telephone network(which may be either analog or digital), a dedicated line network (whichmay be either analog or digital), a CATV network, a portable lineexchange network/portable packet exchange network such as an IMT 2000network, a GSM network, or a PDC/PDC-P network, a wireless call network,a local wireless network such as Bluetooth, a PHS network, and satellitecommunications network such as CD, BS, or ISDB. That is, the presentsystem can transmit and receive various pieces of data through anarbitrary network whether the system is wired or wireless.

As explained so far in detail, the present invention allows a user toset target metabolic circuit information that includes information onnodes respectively representing basic constituent elements of ametabolism and edges respectively representing reaction relationshipsamong the basic constituent elements; allows the user to setenvironmental factor information on an environmental factor thatinfluences both of or one of the basic constituent elements and thereaction relationships; allows the user to set end condition informationon a condition for finishing a simulation; changes both of or one of oneof the nodes and one of the edges included in the target metaboliccircuit information, and executes a metabolic simulation by a metabolicFBA using the set environmental factor information; determines whether aresult of the simulation satisfies the set end condition information,and, if the result of the simulation does not satisfy the end conditioninformation, changes both of or one of another one of the nodes andanother one of the edges, followed by execution of the simulationexecution step; and outputs the result of the executed simulation.Therefore, the present invention can provide a metabolic circuitinformation processing method, a metabolic circuit informationprocessing apparatus, a program, and a recording medium that can realizethe following respects. The user can easily set various conditionsaccording to a user's objective, and a user's target optimum metaboliccircuit information or new metabolic circuit information can be acquiredby performing a simulation processing. By user's setting, for example, atoxic matter such as dioxin or a persistent matter such as plastic as asubstrate (starting material) and obtaining information on an optimummetabolic circuit for metabolizing the substrate, the information can beused for biodegradation of toxic matters and persistent matters. Inaddition, if the user sets an intermediate metabolite or a finalmetabolite such as a low-molecular compound, a sugar, a protein, or anamino acid, then optimum metabolic circuit information for producingmetabolites can be acquired from a simulation result, andpharmaceuticals and foods can be produced using this metabolic circuitinformation. Furthermore, by setting a matter in vivo (e.g., a sugar, aprotein, an amino acid, a DNA, an RNA, or a signal transmitter) andacquiring the metabolic circuit information, knowledge related to adisease or the like caused by a metabolic disorder resulting from thematter in vivo can be acquired.

According to the present invention, each of the basic constituentelements includes information on at least one of a substrate, ametabolite, and a matter in vivo. Therefore, the present invention canprovide a metabolic circuit information processing method, a metaboliccircuit information processing apparatus, a program, and a recordingmedium that can realize the following respects. If the user sets anintermediate metabolite or a final metabolite such as a low-molecularcompound, a sugar, a protein, or an amino acid produced bymicroorganisms, pharmaceuticals, pharmaceutical intermediates, alcohols,amino acids, or the like can be produced with high efficiency byacquiring optimum metabolic circuit information. Furthermore, by settinga matter in vivo (e.g., a sugar, a protein, an amino acid, a DNA, anRNA, or a signal transmitter), new metabolic circuit information relatedto various diseases and the like can be acquired.

According to the present invention, each of the reaction relationshipsincludes information on a relationship of at least one of an enzymereaction, a transcription control reaction, a translation controlreaction, and a chemical reaction between the basic constituentelements. Therefore, the present invention can provide a metaboliccircuit information processing method, a metabolic circuit informationprocessing apparatus, a program, and a recording medium that can realizethe following respects. In relation to the enzyme reaction, for example,information on a synthetic rate and a decomposition rate for the enzymereaction between a substrate and a metabolite can be defined as edgeinformation, and simulation can be carried out based on the information.In relation to the transcription control reaction, information such as atranscription rate, a transcription promoter, and a transcriptioninhibitor for the transcription control reaction between a DNA and anRNA can be defined as edge information, and simulation can be carriedout based on the information. In relation to the translation controlreaction, a translation rate, a translation promoter, and a translationinhibitor for the translation control reaction between an mRNA and aprotein can be defined as edge information, and simulation can becarried out based on the information. In relation to the chemicalreaction, information such as a structural change, a polymerizationproperty, a stability, and a chemical equilibrium for the chemicalreaction between metabolites can be defined as edge information, andsimulation can be carried out based on the information.

According to the present invention, the environmental factor informationincludes information on at least one of a temperature, a pH, anatmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration. Therefore, the present invention canprovide a metabolic circuit information processing method, a metaboliccircuit information processing apparatus, a program, and a recordingmedium that can realize the following respects. Simulation can becarried out based on information on an upper limit and a lower limit ofa temperature, a pH, an atmospheric pressure, the number of times ofstirring, a dissolved oxygen quantity, culture medium components,optical conditions, a carbon dioxide concentration, or the like that isfeasible for an operation in a laboratory or a factory.

According to the present invention, the end condition informationincludes information on at least one of a culture time, a metabolicefficiency, a metabolite quantity, the number of times of simulation, acell density, a culture cost, a pH, a dissolved oxygen quantity, and aculture medium component quantity. Therefore, the present invention canprovide a metabolic circuit information processing method, a metaboliccircuit information processing apparatus, a program, and a recordingmedium that can realize the following respects. If the culture time andthe culture cost, for example, are set as the end condition information,the user can know an optimum simulation result within user's desiredranges of the culture time and the culture cost and thus, metaboliccircuit information usable for actual production can be acquired. Inaddition, if the metabolic efficiency and the metabolite quantity areset as the end condition information, then simulation can be carried outuntil the metabolic efficiency and the metabolite quantity reach atarget efficiency and a target quantity, respectively, and metaboliccircuit information such as culture medium components and culture timenecessary to attain the target metabolic efficiency and the targetmetabolite quantity can be acquired. If the cell density, the pH, thedissolved oxygen quantity, and the culture medium component quantity areset as the end condition information, then simulation can be carried outuntil they reach a set pH, a set culture medium component quantity, andthe like, respectively, and metabolic circuit information in light of achange in a culture state can be acquired. If the number of times ofsimulation is set as the end condition information, optimum metaboliccircuit information can be acquired by executing simulation by a certainnumber of times. Therefore, the disadvantage in that it takesconsiderable long calculation time to acquire the metabolic circuitinformation due to a great calculation quantity can be avoided.

According to the present invention, mutation frequency information on afrequency with which both of or one of the one node and the one edgeincluded in the metabolic circuit information mutates to both of or oneof another one of the nodes and another one of the edges is stored. Bothof or one of the one node and the one edge included in the metaboliccircuit information is changed using the stored mutation frequencyinformation. Therefore, the present invention can provide a metaboliccircuit information processing method, a metabolic circuit informationprocessing apparatus, a program, and a recording medium that canefficiently change metabolic circuit information.

According to the present invention, both of or one of the one node andthe one edge included in the metabolic circuit information is changedusing at least one of a genetic algorithm and simulated annealing.Therefore, the present invention can provide a metabolic circuitinformation processing method, a metabolic circuit informationprocessing apparatus, a program, and a recording medium capable ofefficiently acquiring optimum new metabolic circuit information otherthan stationary-state metabolic circuit information by applying a knownoptimization algorithm.

INDUSTRIAL APPLICABILITY

As explained so far, according to the metabolic circuit informationprocessing method, the metabolic circuit information processingapparatus, the program, and the recording medium according to thepresent invention, by user's setting, for example, a toxic matter suchas dioxin or a persistent matter such as plastic as a substrate(starting material) and obtaining information on an optimum metaboliccircuit for metabolizing the substrate, the information can be used forbiodegradation of toxic matters and persistent matters. In addition, ifthe user sets an intermediate metabolite or a final metabolite such as alow-molecular compound, a sugar, a protein, or an amino acid, thenoptimum metabolic circuit information for producing metabolites can beacquired from a simulation result, and pharmaceuticals and foods can beproduced using this metabolic circuit information. Furthermore, bysetting a matter in vivo (e.g., a sugar, a protein, an amino acid, aDNA, an RNA, or a signal transmitter) and acquiring the metaboliccircuit information, knowledge related to a disease or the like causedby a metabolic disorder resulting from the matter in vivo can beacquired.

1. A metabolic circuit information processing method comprising: ametabolic circuit information setting step of allowing a user to settarget metabolic circuit information that includes information on nodesrespectively representing basic constituent elements of a metabolism andedges respectively representing reaction relationships among the basicconstituent elements; an environmental factor information setting stepof allowing the user to set environmental factor information on anenvironmental factor that influences both of or one of the basicconstituent elements and the reaction relationships; an end conditioninformation setting step of allowing the user to set end conditioninformation on a condition for finishing a simulation; a simulationexecution step of changing both of or one of one of the nodes and one ofthe edges included in the target metabolic circuit information, and ofexecuting a metabolic simulation by a metabolic flux balance analysisusing the environmental factor information set at the environmentalfactor information setting step; a simulation result determination stepof determining whether a result of the simulation executed at thesimulation execution step satisfies the end condition information set atthe end condition information setting step, and of, if the result of thesimulation does not satisfy the end condition information, changing bothof or one of another one of the nodes and another one of the edges,followed by execution of the simulation execution step; and a simulationresult output step of outputting the result of the simulation executedat the simulation execution step.
 2. The metabolic circuit informationprocessing method according to claim 1, wherein each of the basicconstituent elements includes information on at least one of asubstrate, a metabolite, and a matter in vivo.
 3. The metabolic circuitinformation processing method according to claim 1, wherein each of thereaction relationships includes information on a relationship of atleast one of an enzyme reaction, a transcription control reaction, atranslation control reaction, and a chemical reaction between the basicconstituent elements.
 4. The metabolic circuit information processingmethod according to claim 1, wherein the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration.
 5. The metabolic circuit informationprocessing method according to claim 1, wherein the end conditioninformation includes information on at least one of a culture time, ametabolic efficiency, a metabolite quantity, the number of times ofsimulation, a cell density, a culture cost, a pH, a dissolved oxygenquantity, and a culture medium component quantity.
 6. The metaboliccircuit information processing method according to claim 1, furthercomprising: a mutation frequency information storage step of storingmutation frequency information on a frequency with which both of or oneof the one node and the one edge included in the metabolic circuitinformation mutates to both of or one of another one of the nodes andanother one of the edges, wherein at the simulation execution step, bothof or one of the one node and the one edge included in the metaboliccircuit information is changed using the mutation frequency informationstored at the mutation frequency information storage step.
 7. Themetabolic circuit information processing method according to claim 1,wherein at the simulation execution step, both of or one of the one nodeand the one edge included in the metabolic circuit information ischanged using at least one of a genetic algorithm and simulatedannealing.
 8. A metabolic circuit information processing apparatuscomprising: a metabolic circuit information storage unit that storesmetabolic circuit information including information on nodesrespectively representing basic constituent elements of a metabolism andedges respectively representing reaction relationships among the basicconstituent elements; an environmental factor information storage unitthat stores environmental factor information on an environmental factorthat influences both of or one of the basic constituent elements and thereaction relationships; an end condition information storage unit thatstores end condition information on condition for finishing asimulation; a simulation condition setting unit that allows a user toset at least one of the metabolic circuit information, the environmentalfactor information, and the end condition information desired by theuser; a simulation execution unit that changes both of or one of one ofthe nodes and one of the edges included in the metabolic circuitinformation, and executes a metabolic simulation by a metabolic fluxbalance analysis based on at least one of the metabolic circuitinformation set by simulation condition setting unit and theenvironmental factor information until the end condition information setby the simulation condition setting unit is satisfied; and a simulationresult output unit that outputs a result of the simulation executed bythe simulation execution unit.
 9. The metabolic circuit informationprocessing apparatus according to claim 8, wherein each of the basicconstituent elements includes information on at least one of asubstrate, a metabolite, and a matter in vivo.
 10. The metabolic circuitinformation processing apparatus according to claim 8, wherein each ofthe reaction relationships includes information on a relationship of atleast one of an enzyme reaction, a transcription control reaction, atranslation control reaction, and a chemical reaction between the basicconstituent elements.
 11. The metabolic circuit information processingapparatus according to claim 8, wherein the environmental factorinformation includes information on at least one of a temperature, a pH,an atmospheric pressure, the number of times of stirring, a dissolvedoxygen quantity, a culture medium component, an optical condition, and acarbon dioxide concentration.
 12. The metabolic circuit informationprocessing apparatus according to claim 8, wherein the end conditioninformation includes information on at least one of a culture time, ametabolic efficiency, a metabolite quantity, the number of times ofsimulation, a cell density, a culture cost, a pH, a dissolved oxygenquantity, and a culture medium component quantity.
 13. The metaboliccircuit information processing apparatus according to claim 8, furthercomprising: a mutation frequency information storage unit of storingmutation frequency information on a frequency with which both of or oneof the one node and the one edge included in the metabolic circuitinformation mutates to both of or one of another one of the nodes andanother one of the edges, wherein at the simulation execution unit, bothof or one of the one node and the one edge included in the metaboliccircuit information is changed using the mutation frequency informationstored at the mutation frequency information storage unit.
 14. Themetabolic circuit information processing apparatus according to claim 8,wherein at the simulation execution unit, both of or one of the one nodeand the one edge included in the metabolic circuit information ischanged using at least one of a genetic algorithm and simulatedannealing.
 15. A program for allowing a computer to execute a metaboliccircuit information processing method, comprising: a metabolic circuitinformation setting step of allowing a user to set target metaboliccircuit information that includes information on nodes respectivelyrepresenting basic constituent elements of a metabolism and edgesrespectively representing reaction relationships between the basicconstituent elements; an environmental factor information setting stepof allowing the user to set environmental factor information on anenvironmental factor that influences both of or one of the basicconstituent elements and the reaction relationships; an end conditioninformation setting step of allowing the user to set end conditioninformation on a condition for finishing a simulation; a simulationexecution step of changing both of or one of one of the nodes and one ofthe edges included in the target metabolic circuit information, and ofexecuting a metabolic simulation by a metabolic flux balance analysisusing the environmental factor information set at the environmentalfactor information setting step; a simulation result determination stepof determining whether a result of the simulation executed at thesimulation execution step satisfies the end condition information set atthe end condition information setting step, and of, if the result of thesimulation does not satisfy the end condition information, changing bothof or one of another one of the nodes and another one of the edges,followed by execution of the simulation execution step; and a simulationresult output step of outputting the result of the simulation executedat the simulation execution step.
 16. The program according to claim 15,wherein each of the basic constituent elements includes information onat least one of a substrate, a metabolite, and a matter in vivo.
 17. Theprogram according to claim 15, wherein each of the reactionrelationships includes information on a relationship of at least one ofan enzyme reaction, a transcription control reaction, a translationcontrol reaction, and a chemical reaction between the basic constituentelements.
 18. The program according to claim 15, wherein theenvironmental factor information includes information on at least one ofa temperature, a pH, an atmospheric pressure, the number of times ofstirring, a dissolved oxygen quantity, a culture medium component, anoptical condition, and a carbon dioxide concentration.
 19. The programaccording to claim 15, wherein the end condition information includesinformation on at least one of a culture time, a metabolic efficiency, ametabolite quantity, the number of times of simulation, a cell density,a culture cost, a pH, a dissolved oxygen quantity, and a culture mediumcomponent quantity.
 20. The program according to claim 15, furthercomprising: a mutation frequency information storage unit of storingmutation frequency information on a frequency with which both of or oneof the one node and the one edge included in the metabolic circuitinformation mutates to both of or one of another one of the nodes andanother one of the edges, wherein at the simulation execution unit, bothof or one of the one node and the one edge included in the metaboliccircuit information is changed using the mutation frequency informationstored at the mutation frequency information storage unit.
 21. Theprogram according to claim 15, wherein at the simulation execution unit,both of or one of the one node and the one edge included in themetabolic circuit information is changed using at least one of a geneticalgorithm and simulated annealing.
 22. A computer readable recordingmedium that records the program according to claim 15.